Acoziborole-SCYX-7158-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAcoziboroleCat. No.: HY-19910CAS No.: 1266084-51-8Synonyms: SCYX-7158; AN5568分式: CHBFNO分量: 367.1作靶点: Parasite作通路: Anti-infection储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 125 mg/mL (34

2、0.51 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.7241 mL 13.6203 mL 27.2405 mL5 mM 0.5448 mL 2.7241 mL 5.4481 mL10 mM 0.2724 mL 1.3620 mL 2.7241 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果

3、的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 8 mg/mL (21.79 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 8 mg/mL (21.79 mM); Clear solution1/3 Master of Small Molecules 您边的抑制剂师www.MedCh

4、emEBIOLOGICAL ACTIVITY物活性 Acoziborole (SCYX-7158) 可安全按有效地于治疗类洲锥病 (HAT)。作于 T. b. brucei S427菌株，MIC 值为 0.6 g/mL。体外研究 Acoziborole is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense andT. b. gambiense.In whole cell assays, Acoziborole exhibits potent activity

5、against representative T. b. brucei,T. b. rhodesiense and T. b. gambiense strains. IC50 values for Acoziborole are approximately 0.07 g/mL to0.37 g/mL following incubation of the parasite strains with Acoziborole for 72 h. In the T. b. brucei S427strain, the MIC value for Acoziborole is 0.6 g/mL, ap

6、proximately two times the IC50 measured for this strain.In contrast to the potent activity of Acoziborole against trypanosomes, no significant inhibition of cellproliferation is observed in an in vitro mammalian cell (L929 mouse cell line) assay at drug concentrations upto 50 g/mL. The potential for

7、 Acoziborole to inhibit cytochrome P450 (CYP) enzymes is evaluated usingP450-Glo assays for the human isoforms CYP3A4, CYP1A2, CYP2C19, CYP2C9 and CYP2D6. The IC50values for Acoziborole in these assays are all above 10 M 1.体内研究 In uninfected mice, 4.3 mg/kg intravenous dose of Acoziborole show an ap

8、parent elimination half-life (t1/2) of26.6 h; systemic clearance (CL) of 0.089 L/h/kg; a volume of distribution (Vdss) of 1.69 L/kg and area underthe concentration-time curve (AUC0-24 h) of 48 hg/mL. Following an oral dose of 13.4 mg/kg, whichcorresponds to the lowest efficacious dose in the murine

9、stage 2 HAT model, Acoziborole is rapidlyabsorbed, as a Cmax of 6.96 g/mL is achieved in plasma at 6 h after dose, with an oral clearance (Cl/F)value of 0.163 L/h/kg, an AUC0-24 h of 82 hg/mL and absolute oral bioavailability of 55%. After a 26 mg/kgoral dose, which corresponds to the dose giving a

10、100% cure rate in the murine stage 2 HAT model, Cmaxincreases to 9.8 g/mL and the AUC0-24 h is 113 hg/mL. In uninfected rats, following oral administration ofAcoziborole at a nominal dose of 25 mg/kg (dose affording a 100% cure rate in mice), Cmax increasesapproximately 2 fold more than that in mice

11、 (Cmax=18.2 g/mL) and AUC0-24 h, and hence oral clearance,improves approximately 4 fold (AUC0-24 h 291 hg/mL and CL/F=0.092 L/kg/h). The time to maximumconcentration is similar to that in mice (tmax=8 h). Uninfected male and female cynomolgus monkeys aretreated with Acoziborole at 2 mg/kg (IV) on st

12、udy day 1 and 10 mg/kg (NG) on study day 8. Acoziboroleexhibits excellent plasma pharmacokinetics, with CL of 0.022 L/h/kg; Vdss of 0.656 L/kg and area under theconcentration-time curve 78.8 hg/mL, and 94.4 for AUC0-24 h and AUC0-inf, respectively, followingintravenous administration 1.PROTOCOLCell

13、Assay 1 Compounds (e.g., Acoziborole) to be tested are serially diluted in DMSO and added to 96-well plates to givefinal concentrations ranging from 5 to 0.01 g/mL. T. b. brucei parasites in the log phase of growth are dilutedin HMI-9 media and added to each well for a final concentration of 1104 pa

14、rasites per well. For thesensitivity assays using T. b. rhodesiense and T. b. gambiense, pararasites are cultured in MEMsupplemented with Baltz components, diluted in the aforementioned culture media, and added to each well ata density of 1103 cells/well. The final concentration of DMSO is 0.5% and

15、the total volume is 100 L/well.After 72 h incubation, Resazurin is added to each well (20 L of 25 mg/100 mL stock in PBS) and incubated2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEfor an additional 4-6 h. To assess cell viability, fluorescence is quantified using an EnVision Multilabel PlateRead

16、er at an excitation wavelength of 530 nm and emission of 590 nm. Triplicate data points are averaged togenerate sigmoidal dose-response curves and determine IC50 values using XLfit curve fitting software. TheIC50 is defined as the amount of compound required to decrease parasite or cell viability by

17、 50% comparedto those grown in the absence of the test compound. The MIC, defined as the lowest concentration ofcompound that completely inhibits visible parasite growth, is determined by visual inspection of 96-well platesafter 48-72 h of incubation with the test compounds. To evaluate the effects

18、of serum on trypanocidal activity,assays are performed in the presence of increasing concentration (2.5% to 50%) of fetal calf serum. Theresults are expressed as a fold-change in IC50 values relative to standard conditions (10% FCS) 1.MCE has not independently confirmed the accuracy of these methods

19、. They are for reference only.Animal Mice, Rats and Monkeys 1Administration 1 Male CD-1 mice (25 g), male Sprague-Dawley rats (225 g), or male cynomolgus monkeys (3-5 kg) areadministered test article by either bolus intravenous injection (IV) or oral gavage. Male CD-1 mice, Sprague-Dawley rats, cynomolgus monkeys or male beagle d